Immunologic approaches to cancer therapy are based on the notion that cancer cells have somehow evaded the body's defenses against aberrant or foreign cells and molecules, and that these defenses might be therapeutically stimulated to kill or inhibit the growth of the cancer cells, e.g., as discussed by Klein (Immunology, Wiley-Interscience, New York, 1982, pp. 623-648). The recent observation that immune effectors can directly or indirectly inhibit tumor growth has led to renewed interest in this approach to cancer therapy Heberman, Concepts Immunopath. 1:96 (1985) (natural killer cells resist tumor growth); Rosenberg et al., Ann. Rev. Immunol. 4:681 (1988) (use of IL-2-activated killer cells to treat cancer); Ralf et al., J. Exp. Med. 167:712 (1988) (tumoricidal activity of macrophages stimulated by lymphokines); Tepper et al., Cell 57:503 (1989) (IL-4 has tumoricidal activity); M. Cohen, "Lymphokines and Tumor Immunity", pp. 237-253, in S. Cohen, ed., Lymphokines and the Immune Response (CRC Press, Boca Raton, 1990)!.
Immune responsiveness to neoplasms is regulated by a variety of cell types and involves the actions of T-cell and monocyte-derived cytokines. One immunologic approach that has shown clinical promise has been so-called "adoptive immunotherapy" using IL-2-activated killer cells Rosenberg, supra; Rosenberg, Sci. Am., pp. 62-69 (May 1990)!. Although IL-2 alone or in combination with more traditional chemotherapeutic agents appears to be effective in treating certain malignancies (e.g., renal cell carcinoma), unfortunate toxic side effects such as vascular bed leakage and edema associated with administration of effective dosages of IL-2 have led some to suggest that the risks may outweigh the benefits Cotran et al., J. Immunol. 139:1882 (1987); Edwards et al., Cancer Res. 52:3425 (1992)!.
Human vascular endothelial cells appear to be particularly sensitive to IL-2 toxicity, as evidenced by increased vascular permeability (i.e. vascular leak syndrome) and edema. One of the factors contributing to this pathology may be augmented adhesion of IL-2-activated T cells and neutrophils to endothelial monolayers, as has previously been noted in vitro Edwards et al., supra; Damle et al., 138:1779 (1987)!.
An alternative therapeutic approach to the immunologic treatment of neoplastic disease is the adoptive transfer of immune cells. Adoptive immunotherapy is defined as the transfer to a tumor-bearing host of active immunologic reagents, such as cells with anti-tumor activity that can mediate, either directly or indirectly, anti-tumor effects. Adoptive immunotherapy represents an attractive approach to the therapy of neoplastic disease. It should be noted that because active immunologic reagents are being transferred to the host, complete host immunocompetence is not required. Thus, the immunosuppression generally associated with the tumor-bearing state does not represent a major problem to this therapeutic alternative. Since host immunocompetence is not required, and in fact may be beneficial to the effects of the adoptive transfer of immune cells, adoptive immunotherapy can easily be combined with other therapies such as chemotherapy or radiation therapy. Also, in contrast to other therapies, immunosuppression is unlikely to result from this treatment.
Patients undergoing chemotherapy or radiation therapy tend to be immunocompromised and will generally have a depleted supply of effector peripheral blood mononuclear cells (PBMCs) available for activation. A therapy that shows efficacy at low effector cell:target cell ratios would thus be particularly advantageous for such patients.
Immune responsiveness to neoplasms is regulated by a variety of cell types and involves the actions of T-cell and monocyte-derived cytokines. Adoptive immunotherapy using recombinant human cytokines has involved administration of peripheral blood mononuclear cells (PBMCs) stimulated extra-corporeally Phillips et al., J. Clin. Oncol. 5:1933:(1987); Perussia, Curr. Opin. Immunol. 3:49:(1991)! followed by administration of IL-2 Rosenberg et al., J. Immunol. 138:1779 (1985)!. The extra-corporeal treatment of the PBMCs produces activated lymphokine-activated killer (LAK) cells and activated natural killer (NK) cells having cytolytic activity for various tumor cells.
Recombinant human IL-5 Nagasawa et al., Cell. Immunol. 133:317 (1991)!, IL-7 Stotter and Lotze, Arch. Surgery 126:1525 (1991)! and IL-12 Gately et al., J. Immunol. 147:874 (1991)! have been reported to stimulate cytolytic activity in human PBMCs. Interleukin-10 (IL-10), originally described in mice as a cytokine synthesis inhibitory factor secreted by specific helper T-cell subsets, appears to modulate the differentiation of murine cytotoxic T-cells Chen and Zlotnik, J. Immunol 147:528 (1991)!. It has also been found that human PBMCs incubated with supernatants recovered from COS cells transfected with the human IL-10 cDNA lysed tumor cell targets in vitro. The T cells responding to IL-10 with increased cytolytic potential were identified to be of a CD56+ phenotype, indicative of NK cells.
In some circumstances, IL-4 can adversely affect the generation of LAK activity by IL-2 Nagler et al., J. Immunol. 141:2349 (1988)!. For example, if human PBMCs are cultured in the presence of both IL-2 and IL-4, the lysis of LAK-sensitive targets is greatly reduced Spits et al., J: Immunol. 141:29 (1988)!. If the PBMCs are pre-cultured in medium supplemented with IL-2 for 3 days before adding IL-4, however, augmented cytolytic activity results Spits et al., supra!. Moreover, the blockade of IL-2-driven cytotoxicity by IL-4 can be abated when alpha-interferon (.alpha.-IFN) or tumor necrosis factor-alpha (TNF-.alpha.) is included in the initial incubation mixture Swisher et al., Cell. Immunol. 128:450 (1990)!.
Kedar et al., Cancer Immunol. Immunother. 35:63 (1992)! have recently indicated that sequential administration of IL-2 and .alpha.-IFN is an effective immunotherapeutic regimen for treatment of MCA-105 sarcomas and M109 carcinomas in murine tumor models. The primary finding from this study was that sequential administration of cytokines appeared to have greater efficacy than concomitant administration of both cytokines.
The feasibility and efficacy of adoptive immunotherapy as a treatment modality for various diseases, particularly for the treatment of neoplastic disease (cancer) in humans, have been described in U.S. Pat. No. 4,690,915 to Rosenberg. As already noted above, however, there is a need for methods for carrying out such treatments that are not as toxic as those employing IL-2 alone. There is also a need for a therapy that is effective at low effector cell:target cell ratios.